1. Field of the Invention:
The present invention relates to methods and compositions useful in the treatment and diagnosis of autoimmune diseases and more particularly to such methods and compositions produced by genetic engineering.
2. Description of the Prior Art:
In normal humans and animals an individual will respond to exposure to a foreign substance by the production of specific antibodies or by developing cell-mediated immunity against the foreign substance. Individuals are generally tolerant of substances which normally form a part of themselves and are thus described as being self-tolerant. The development of an immunologic response to self is called autoimmunity and is the result of some breakdown of self-tolerance.
Various theories have been proposed to explain the development of autoimmunity. For example, viruses are thought to play an important role in the pathogenesis of autoimmunity as has been demonstrated in several animal models. The expression of viral antigens on the surface of the host cells may elicit autoantibodies to cell antigens as well as to the viral antigens. It has also been proposed that autoimmunity is a disorder caused by abnormal immunologic regulation, particularly a change in T-cell activity. A decrease in suppressor T-cell activity or an increase in helper T-cell activity would result in excess production of autoantibodies. This theory finds support in the finding of autoantibodies in some normal persons without evidence of autoimmune disease and in various animal models. Gene control also appears to exist in at least some autoimmune diseases as certain micestrains have been demonstrated to exhibit an autoimmune disease similar to systemic lupus erythematosus (SLE). A high correlation of SLE is also found in identical twins. Additionally, an association of autoimmune disease with genes located in the HLA-D locus has been noted in adult rheumatoid arthritis and in multiple sclerosis.
Systemic lupus erythematosus (SLE) is a serious autoimmune disease which affects the collagen of the connective tissues of the human body. Since SLE may affect one or more of a large number of different tissues or organs of the body, such as blood vessels, heart, kidneys, skin, serous membranes, etc., clinical diagnosis of SLE is often difficult since the symptoms may resemble a number of other diseases such as rheumatoid arthritis, skin cancer, serum sickness, rheumatic fever, multiple myeloma, and Sjogren's syndrome.
It is important to be able to distinguish SLE from other diseases due to the high probability of kidney, central nervous system, and vascular damage from the disease. For example, lupus nephritis is very frequent in the disease and is one of the most serious features of SLE. Nephritis is a frequent cause of death in SLE patients, and it would be most advantageous to be able to detect SLE early enough to prevent or mitigate serious kidney damage.
It has been demonstrated that sera from patients with connective tissue disorders contain antibodies to many nuclear constituents. For example, circulating antibodies that react with native DNA (deoxyribonucleic acid) have been found to be highly specific to patients suffering from systemic lupus erythematosus. The appearance and exacerbation of the nephritis attendant in SLE appears to be related to the formation and deposition of antibody/DNA and other immune complexes in the kidneys and particularly the renal glomeruli. Although the exact reasons for the production of these antibodies and the reasons for their particular specificity to SLE are as yet unknown, the detection and measurement of these autoantibodies has become increasingly important in the clinical diagnosis and evaluation of this disease.
Recently, a precise method for measuring various small amounts of anti-DNA antibody has been developed using C.sup.14 -labeled DNA. See T. Pincus et al, "Measurement of Serum DNA-Binding Activity In Systemic Lupus Erythematosus," New England Journal of Medicine, 281,701-705 (1969). This method appears to be the most definitive test for SLE presently available. It is reported to be positive in 75 percent of SLE patients studied, whereas other leading tests were positive in only about 25-64 percent of SLE cases. Moreover, this anti-DNA antibody test has shown greater specificity for SLE than other diagnostic tests used, such as immunodiffusion, complement-fixation, and precipitation. Normal sera also often reacts with DNA.
However, this test is a test for antibodies that react with DNA although DNA may not be the authentic antigen. Furthermore, this method is not applicable to autoimmune disorders in which the antigen is a protein. Protein antigens are associated with most forms of SLE as well as other types of autoimmune diseases. Such protein antigens are useful in disease classification, diagnostic and treatment methods as a result of the ability to react specifically with autoantibodies associated with an autoimmune disease. However, isolation and purification of these antigens have heretofore not been fruitful because of the scarcity and instability of antigenic material and because of the complexity of the separation techniques. Accordingly, a method for producing protein antigens which are reactive with an autoantibody associated with an autoimmune disease in a host is still needed.